Median Nerve Stimulation Pilot

NCT04731714 | Completed Results FDA Device

• 2 other identifiers: 202011092UL1TR002345
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

Results from the University of Nottingham suggested that rhythmic median nerve stimulation (MNS) improves tic symptoms in Tourette syndrome (TS). The investigators will (1) provide a first replication of their study, (2) test the hypothesized electrophysiological mechanism and rule out a placebo effect as cause for the symptomatic benefit, and (3) gather information on the duration of effect after the end of stimulation and on individual characteristics that predict improvement with simulation. Completion of these Aims will give a clear go/no-go signal for a future clinical trial of chronic MNS delivered by a yet-to-be-developed wristwatch-style device. NOTE: This study is not intended to evaluate a specific device for future use. Rather it is a study to determine the action of pulsed electrical stimulation on tic symptoms and to gain early evidence of effectiveness. This is a non-significant risk device study.

Conditions

Tourette Syndrome; Tic Disorders; Tic Disorder, Chronic Motor or Vocal

Keywords

Tourette; Tic; Transcutaneous Electric Nerve Stimulation; Median Nerve

Outcome Measures

Primary Outcomes (4)

• Change in Tic Frequency From When MNS is Turned Off

  The number of tics per minute is assessed by an expert rater blind to condition and time point. Mean tic frequency was compared in on vs. off 1-minute stimulation epochs on the rhythmic MNS day. This analysis replicates that of Study 3 in the Morera Maiquez et al 2020 citation, who reported tics in the last 40 seconds of the block to minimize carryover effects. A Mixed Models Analysis was used to test statistical significance; it included a factor for possible within-day carryover effect and used a logarithmic transformation for tic count. Data reported here have been back-transformed to the number of tics in the last 40 s of the stimulation blocks.

  During the 1-minute on and 1-minute off blocks of rhythmic MNS stimulation (total 4 blocks)

• Change in Tic Severity From When MNS is Turned Off

  Severity is rated on a 5-point scale for each occurrence of any tic. The scale is the Intensity item from the Yale Global Tic Severity Scale \[YGTSS\], which uses integer scores from 0 (no tics) to 5 (severe intensity). Mean tic severity was compared in on vs. off 1-minute stimulation epochs on the rhythmic MNS day. This analysis replicates that of Study 3 in the Morera Maiquez et al 2020 citation.

  During the 1-minute on and 1-minute off blocks of rhythmic MNS stimulation (total 4 blocks)

• Change in Tic Frequency During Rhythmic MNS (vs. Arrhythmic MNS)

  The number of tics per minute is assessed by an expert rater blind to condition and time point. Change in tic frequency from baseline (stimulation off) is compared between 5-minute MNS-on epochs on the rhythmic vs. the arrhythmic day. Subjects who do not complete both stimulation visits will not be included in this analysis. The hypothesized change is greater improvement (off to on) with rhythmic vs. arrhythmic stimulation. This analysis includes the first six 5-minute blocks on each MNS day (i.e., the blocks that all participants complete). MNS was administered throughout blocks 6 and 8 only. Tic frequency in block 0 (baseline, before any stimulation) on the same day was a covariate in the statistical model.

  During 5-minute MNS stimulation on or off blocks 0, 5, 6, 7, 8 and 9

• Change in Tic Severity During Rhythmic MNS (vs. Arrhythmic MNS)

  Overall tic severity for each 5-minute block is rated once on a 5-point scale by an expert blind to condition and time point. The scale is the Intensity item from the Yale Global Tic Severity Scale \[YGTSS\], which uses integer scores from 0 (no tics) to 5 (severe intensity). Change in tic severity from baseline (stimulation off) is compared between 5-minute MNS-on epochs on the rhythmic vs. the arrhythmic day. Subjects who do not complete both stimulation visits will not be included in this analysis. The hypothesized change was greater improvement (off to on) with rhythmic vs. arrhythmic stimulation. This analysis includes the first six 5-minute blocks on each MNS day (i.e., the blocks that all participants complete). MNS was administered throughout blocks 6 and 8 only. Tic frequency in block 0 (baseline, before any stimulation) on the same day was a covariate in the statistical model.

  During 5-minute MNS stimulation on or off blocks 0, 5, 6, 7, 8 and 9

Secondary Outcomes (7)

• Change in Tic Severity After MNS Ends

  up to 20 minutes after the end of stimulation at each study visit up to 1 month

• CGI-I, Participant

  5-25 minutes after the end of stimulation at each study visit up to 1 month

• CGI-I, Investigator

  5-25 minutes after the end of stimulation at each study visit up to 1 month

• Rating of Therapeutic Effect Using the CGI Efficacy Index

  5-25 minutes after the end of stimulation at each study visit up to 1 month

• VAS (Visual Analog Scale) Rating of Premonitory Urge Severity

  At the end of each 5-min. MNS on or off block through block 9, at each study visit

Study Arms (2)

Experimental: rhythmic MNS, then arrhythmic MNS

OTHER

Participants will complete two stimulation sessions, at least a week apart. The first session involves rhythmic MNS and the second uses arrhythmic MNS.

Device: Rhythmic median nerve stimulation; Device: Arrhythmic median nerve stimulation

Experimental: arrhythmic MNS, then rhythmic MNS

OTHER

Participants will complete two stimulation sessions, at least a week apart. The first session involves arrhythmic MNS and the second uses rhythmic MNS.

Device: Rhythmic median nerve stimulation; Device: Arrhythmic median nerve stimulation

Interventions

Rhythmic median nerve stimulation DEVICE

Square-wave 200 µs pulses triggered by computer at 12 Hz, at the threshold for thumb movement (expected \~2-15mA), applied to surface electrodes over the median nerve at the right wrist (conductive gel, 30 mm apart center-to-center, anode distal). This is a non-significant risk device study.

Also known as: Rhythmic MNS

Experimental: arrhythmic MNS, then rhythmic MNS; Experimental: rhythmic MNS, then arrhythmic MNS

Arrhythmic median nerve stimulation DEVICE

Square-wave 200 µs pulses triggered by computer at random intervals with a mean rate of 12 Hz (as described in Morera Maiquez et al., 2020), at the threshold for thumb movement (expected \~2-15mA), applied to surface electrodes over the median nerve at the right wrist (conductive gel, 30 mm apart center-to-center, anode distal). This is a non-significant risk device study.

Also known as: Arrhythmic MNS

Experimental: arrhythmic MNS, then rhythmic MNS; Experimental: rhythmic MNS, then arrhythmic MNS

Eligibility Criteria

• Age: 15 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age 15-64 inclusive at initial screening visit
• Informed consent by adult subject; assent by child and informed consent by guardian
• Current Tourette's Disorder or Persistent (Chronic) Tic Disorder according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition: DSM-5
• At least 1 tic per minute (average) during the first 5-min. baseline video session on the first visit (as scored during the session by the investigator)

You may not qualify if:

• Unable to complete study procedures for any reason
• Has an implanted device that could be affected by electrical current
• Pregnancy known to participant or (for children) to the parent
• Known or suspected primary genetic syndrome (e.g. Down syndrome, Fragile X)
• Intellectual disability (known, or likely from history and examination)
• Head trauma with loss of consciousness for more than 5 minutes
• Significant neurologic disease, not counting TS (exceptions include febrile seizures or uncomplicated migraine)
• Severe or unstable systemic illness
• Factors (such as exaggerated signs) that in the judgment of the principal investigator make the video recording or YGTSS an inaccurate assessment of tic severity
• Judged by investigator to be unlikely to complete study procedures or to return for later visits
• Change in somatic or psychotherapeutic treatment in the 2 weeks preceding the first stimulation visit
• Planned change in somatic or psychotherapeutic treatment between the 2 stimulation visits

Sponsors & Collaborators

• Washington University School of Medicine: lead
• National Center for Advancing Translational Sciences (NCATS): collaborator

Study Sites (1)

Washington University School of Medicine, Movement Disorders Center

St Louis, Missouri, 63110, United States

Location

Related Publications (3)

• Morera Maiquez B, Sigurdsson HP, Dyke K, Clarke E, McGrath P, Pasche M, Rajendran A, Jackson GM, Jackson SR. Entraining Movement-Related Brain Oscillations to Suppress Tics in Tourette Syndrome. Curr Biol. 2020 Jun 22;30(12):2334-2342.e3. doi: 10.1016/j.cub.2020.04.044. Epub 2020 Jun 4.

  PMID: 32502412 BACKGROUND

• Iverson AM, Arbuckle AL, Ueda K, Song DY, Bihun EC, Koller JM, Wallendorf M, Black KJ. Median Nerve Stimulation for Treatment of Tics: Randomized, Controlled, Crossover Trial. J Clin Med. 2023 Mar 27;12(7):2514. doi: 10.3390/jcm12072514.

  PMID: 37048598 DERIVED

• Iverson AM, Arbuckle AL, Ueda K, Song DY, Bihun EC, Koller JM, Wallendorf M, Black KJ. Peripheral nerve induction of inhibitory brain circuits to treat Tourette syndrome: A randomized crossover trial. medRxiv [Preprint]. 2023 Feb 6:2023.02.01.23285304. doi: 10.1101/2023.02.01.23285304.

  PMID: 36778375 DERIVED

Related Links

• Study protocol (follow link under "Protocol")

MeSH Terms

Conditions

Tourette Syndrome; Tic Disorders; Tics

Condition Hierarchy (Ancestors)

Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Neurodevelopmental Disorders; Mental Disorders; Dyskinesias; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

We did not test other variations on MNS, so we cannot address the specificity of the median nerve (vs. any other peripheral nerve), the specificity of 10-12 Hz as the stimulation frequency, or whether there is a lateral preference for MNS benefit.

Results Point of Contact

• Title: Kevin J. Black, M.D.
• Organization: Washington University School of Medicine

kevin@wustl.edu

314-362-5041

Study Officials

• Kevin J Black, MD

  Washington University Medical School

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The stimulation pulses will be triggered by a computer program which will provide either rhythmic or arrhythmic MNS at the same mean rate throughout a given study session. A programmer who does not interact with the participants uses a stimulation order table created by a true random number generator to select the "day 1" and "day 2" program for each participant in advance. Participants and the investigator are blind to stimulation order and stimulation type. Audiovisual recordings of tics will be rated by a reviewer who will additionally be blind to time (first vs. second stimulation session).
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: After screening and characterizing symptoms and other demographic and clinical features, all participants will complete two stimulation sessions, at least a week apart. These are identical except that one session uses rhythmic and one uses arrhythmic MNS with the same number of total pulses per minute. Session order is randomized and participants are blinded to order. Biological carryover effects are very unlikely. Tics before, during and after stimulation epochs are video recorded for later analysis blind to time, stimulation (on vs. off), and stimulation type (rhythmic vs. arrhythmic). NOTE: This study is not intended to evaluate a specific device for future use. Rather it is a study to determine the action of pulsed electrical stimulation on tic symptoms and to gain early evidence of effectiveness. This is a non-significant risk device study.

Study Record Dates

• First Submitted: January 13, 2021
• First Posted: February 1, 2021
• Study Start: July 15, 2021
• Primary Completion: April 27, 2022
• Study Completion: April 27, 2022
• Last Updated: October 5, 2023
• Results First Posted: October 5, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: The study protocol is available now (https://osf.io/mtbzf/). Statistical Analysis Plan (SAP) will be available before enrolling the first participant.
• Access Criteria: Individual participant data (IPD) will be freely available under a CC0 license (Creative Commons public domain dedication, https://creativecommons.org/publicdomain/zero/1.0/).

Locations

US (1)